Non-canonical MAPK signaling in yeast

酵母中的非典型 MAPK 信号传导

• 批准号: 10468756
• 负责人: EDWARD P WINTER
• 金额: $ 32.14万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468756
• 关键词: Alzheimer' s Disease; Anaphase; Animals; Apoptosis; Binding; Binding Proteins; Biochemistry; Biological Models; Cell Cycle; Cell Nucleus; Cells; Cellular biology; Chromosome Segregation; Complex; Congenital Abnormality; Coupled; Couples; Coupling; Cues; Cyclic AMP-Dependent Protein Kinases; Cytoplasm; Data; Development; Disease; Down-Regulation; Enzymes; Eukaryota; Event; Family; G0 Phase; Germ Cells; Glucans; Health; Human; Life Cycle Stages; Link; Lobe; MAP Kinase Gene; MAPK8 gene; Malignant Neoplasms; Mediating; Meiosis; Membrane; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Mitogens; Modeling; Molecular Conformation; Molecular Genetics; Nuclear; Pathway interactions; Phase; Phosphorylation; Phosphotransferases; Play; Process; Property; Proteins; RNA Recognition Motif; Regulation; Reproduction spores; Research; Role; Saccharomyces cerevisiae; Signal Pathway; Signal Transduction; Specificity; Stimulus; Testing; Threonine; Time; Tyrosine; Yeasts; anaphase-promoting complex; cell growth; cyclin-dependent kinase-activating kinase; environmental stressor; human disease; inhibitor; insight; link protein; p38 Mitogen Activated Protein Kinase; prevent; programs; recruit; segregation; spatiotemporal; ubiquitin-protein ligase

Project Summary/Abstract: Mitogen activated protein kinases (MAPKs) are a family of conserved signaling enzymes that are dysregulated in numerous human diseases. Many MAPKs are activated in canonical signaling pathways by MAPK kinases. This mechanism of activation has been well-studied. Other MAPKs are activated in non- canonical signaling pathways by binding proteins that trigger autophosphorylation of the MAPK. Relatively little is known about this mechanism of activation and how it is regulated. The yeast Saccharomyces cerevisiae is a powerful model system in which to study MAPK signaling. Smk1 is a meiosis-specific MAPK in yeast that is activated in a non-canonical pathway by a binding protein, Ssp2, as the meiotic divisions are being completed. Smk1 then controls the post-meiotic program of gamete (spore) formation by phosphorylating regulatory substrates. The anaphase promoting complex (APC) E3 ubiquitin-ligase is a key regulator of chromosome segregation. The APC also plays a role in coupling the differentiation of animal cells to the G1/G0 phase of the cell-cycle. The APC is required for Ssp2 to activate Smk1 yet the mechanism linking the APC to MAPK activation was until recently unknown. In preliminary data, Isc10 has been identified as an inhibitory protein that links the APC to Smk1 activation. A working model for this pathway posits that Isc10 forms a complex with Smk1 and Ssp2 in the cytoplasm of meiotic cells that is poised for activation. In this model, the poised ternary complex is imported into nuclei, where the nuclear resident APC, complexed with a meiosis-specific targeting subunit, Ama1, triggers ubiquitylation of Isc10 after anaphase of meiosis II. This allows Ssp2 to activate the intramolecular autophosphorylation of Smk1, thereby activating the MAPK and coupling spore differentiation to the completion of nuclear segregation. To test and extend this model we will: 1- Elucidate how the inhibitor protein Isc10 controls Smk1 activation, 2- Decipher the spatiotemporal regulation that links MAPKs to the APC, 3- Determine how activated Smk1 controls post-meiotic processes. Insights from these studies will be broadly relevant to mechanisms that control MAPK signaling in the context of developmental programs and how the APC couples differentiation programs to the cell-cycle in higher eukaryotes.

项目摘要/摘要：丝裂原激活蛋白激酶 (MAPK) 是一个家族 在许多人类疾病中失调的保守信号酶。许多 MAPK 在经典信号传导通路中被 MAPK 激酶激活。这 激活机制已得到充分研究。其他 MAPK 在非 通过结合触发自磷酸化的蛋白质的经典信号传导途径 映射。人们对这种激活机制及其具体原理知之甚少 受监管。酿酒酵母是一个强大的模型系统，在其中 研究 MAPK 信号传导。 Smk1 是酵母中减数分裂特异性的 MAPK，在 随着减数分裂的进行，结合蛋白 Ssp2 的非规范途径 完全的。 Smk1 然后通过以下方式控制配子（孢子）形成的减数分裂后程序： 磷酸化调节底物。后期促进复合物 (APC) E3 泛素连接酶是染色体分离的关键调节因子。 APC 还扮演着 在将动物细胞分化与细胞周期的 G1/G0 期耦合中发挥作用。 Ssp2 需要 APC 来激活 Smk1，但将 APC 链接到的机制 MAPK 的激活直到最近才为人所知。初步数据显示，Isc10 被鉴定为一种将 APC 与 Smk1 激活联系起来的抑制蛋白。一个工作模型 因为该途径假设 Isc10 与细胞质中的 Smk1 和 Ssp2 形成复合物 准备激活的减数分裂细胞。在这个模型中，平衡的三元复合体是 输入到细胞核中，其中核驻留的 APC 与减数分裂特异性的复合物 减数分裂 II 后期后，靶向亚基 Ama1 触发 Isc10 泛素化。 这使得Ssp2能够激活Smk1的分子内自磷酸化，从而 激活 MAPK 并将孢子分化与核的完成耦合起来 隔离。为了测试和扩展这个模型，我们将： 1- 阐明抑制剂蛋白如何 Isc10 控制 Smk1 激活，2-破译链接的时空调节 MAPK 到 APC，3-确定激活的 Smk1 如何控制减数分裂后过程。 这些研究的见解将与 MAPK 的控制机制广泛相关 发育程序背景下的信号传递以及 APC 如何耦合 高等真核生物细胞周期的分化程序。